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Trained innate immunity: a salient factor in the pathogenesis of neuroimmune psychiatric disorders

Molecular Psychiatry volume 23, pages 170–176 (2018)Cite this article

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Abstract

Historically, only cells of the adaptive immune system have been considered capable of retaining memory for infectious challenges. Recently, however, cells of the innate immune system have been shown to be capable of displaying long-term functional memory following a single immunostimulatory challenge, leading to enhanced production of proinflammatory molecules upon other subsequent, and temporally distant, immunostimulatory challenges. This effect has been termed ‘trained innate immunity’, and is underwritten by stable epigenetic changes in immune and metabolic pathways. Importantly, the long-term training of innate immune cells can occur as a result of infectious as well as and non-infectious challenges, including stress. Given the role that both stress and an activated immune system have in neuropathology, innate immune training has important implications for our understanding and treatment of neuropsychiatric disorders. This review focuses on the evidence for trained innate immunity and highlights some insights into its relevance for psychiatric diseases.

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References

  1. Khandaker GM, Cousins L, Deakin J, Lennox BR, Yolken R, Jones PB . Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry 2015; 2: 258–270.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Jeon SW, Kim YK . Neuroinflammation and cytokine abnormality in major depression: Cause or consequence in that illness? World J Psychiatry 2016; 6: 283–293.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Aricioglu F, Ozkartal CS, Unal G, Dursun S, Cetin M, Müller N . Neuroinflammation in schizophrenia: a critical review and the future. Klinik Psikofarmakoloji Bulteni 2016; 26: 429–437.

    Article  Google Scholar 

  4. Jones KA, Thomsen C . The role of the innate immune system in psychiatric disorders. Mol Cell Neurosci 2013; 53: 52–62.

    Article  CAS  PubMed  Google Scholar 

  5. Najjar S, Pearlman DM, Alper K, Najjar A, Devinsky O . Neuroinflammation and psychiatric illness. J Neuroinflammation 2013; 10: 43.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Lull ME, Block ML . Microglial activation and chronic neurodegeneration. Neurotherapeutics 2010; 7: 354–365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Borsini A, Zunszain PA, Thuret S, Pariante CM . The role of inflammatory cytokines as key modulators of neurogenesis. Trends Neurosci 2015; 38: 145–157.

    Article  CAS  PubMed  Google Scholar 

  8. Bakunina N, Pariante CM, Zunszain PA . Immune mechanisms linked to depression via oxidative stress and neuroprogression. Immunology 2015; 144: 365–373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Streit WJ, Mrak RE, Griffin WST . Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 2004; 1: 14.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Beumer W, Gibney SM, Drexhage RC, Pont-Lezica L, Doorduin J, Klein HC et al. The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. J Leukoc Biol 2012; 92: 959–975.

    Article  CAS  PubMed  Google Scholar 

  11. Perry VH, Nicoll JAR, Holmes C . Microglia in neurodegenerative disease. Nat Rev Neurol 2010; 6: 193–201.

    Article  PubMed  Google Scholar 

  12. Yirmiya R, Rimmerman N, Reshef R . Depression as a microglial disease. Trends Neurosci 2015; 38: 637–658.

    Article  CAS  PubMed  Google Scholar 

  13. Soczynska JK, Mansur RB, Brietzke E, Swardfager W, Kennedy SH, Woldeyohannes HO et al. Novel therapeutic targets in depression: minocycline as a candidate treatment. Behav Brain Res 2012; 235: 302–317.

    Article  CAS  PubMed  Google Scholar 

  14. Zheng X, Zhang X, Wang G, Hao H . Treat the brain and treat the periphery: toward a holistic approach to major depressive disorder. Drug Discov Today 2015; 20: 562–568.

    Article  PubMed  Google Scholar 

  15. Delves PJ, Martin SJ, Burton DR, Roitt IM . Roitt's Essential Immunology. John Wiley & Sons, 2011.

    Google Scholar 

  16. Netea MG, Latz E, Mills KHG, O'Neill LAJ . Innate immune memory: a paradigm shift in understanding host defense. Nat Immunol 2015; 16: 675–679.

    Article  CAS  PubMed  Google Scholar 

  17. Netea MG, Quintin J, van der Meer JWM . Trained Immunity: a memory for innate host defense. Cell Host Microbe 2011; 9: 355–361.

    Article  CAS  PubMed  Google Scholar 

  18. van 't Wout JW, Poell R, van Furth R . The role of BCG/PPD-activated macrophages in resistance against systemic candidiasis in mice. Scand J Immunol 1992; 36: 713–719.

    Article  CAS  PubMed  Google Scholar 

  19. Bistoni F, Verducci G, Perito S, Vecchiarelli A, Puccetti P, Marconi P et al. Immunomodulation by a low-virulence, agerminative variant of Candida albicans. Further evidence for macrophage activation as one of the effector mechanisms of nonspecific anti-infectious protection. J Med Vet Mycol 1988; 26: 285–299.

    Article  CAS  PubMed  Google Scholar 

  20. Condliffe AM, Kitchen E, Chilvers ER . Neutrophil priming: pathophysiological consequences and underlying mechanisms. Clin Sci 1998; 94: 461–471.

    Article  CAS  Google Scholar 

  21. Netea MG . Training innate immunity: the changing concept of immunological memory in innate host defence. Eur J Clin Invest 2013; 43: 881–884.

    Article  CAS  PubMed  Google Scholar 

  22. Schroder K, Sweet MJ, Hume DA . Signal integration between IFNγ and TLR signalling pathways in macrophages. Immunobiology 2006; 211: 511–524.

    Article  CAS  PubMed  Google Scholar 

  23. Perry VH, Holmes C . Microglial priming in neurodegenerative disease. Nat Rev Neurol 2014; 10: 217–224.

    Article  CAS  PubMed  Google Scholar 

  24. Ransohoff RM, Perry VH . Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 2009; 27: 119–145.

    Article  CAS  PubMed  Google Scholar 

  25. Wynne AM, Henry CJ, Godbout JP . Immune and behavioral consequences of microglial reactivity in the aged brain. Integr Comp Biol 2009; 49: 254–266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kleinnijenhuis J, Quintin J, Preijers F, Benn CS, Joosten LAB, Jacobs C et al. Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity. J Innate Immun 2014; 6: 152–158.

    Article  CAS  PubMed  Google Scholar 

  27. Ramirez K, Shea DT, McKim DB, Reader BF, Sheridan JF . Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance. Brain Behav Immun 2015; 46(C): 212–220.

    Article  PubMed Central  Google Scholar 

  28. Saeed S, Quintin J, Kerstens HHD, Rao NA, Aghajanirefah A, Matarese F et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 2014; 345: 1251086–1251086.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Poli A, Kmiecik J, Domingues O, Hentges F, Blery M, Chekenya M et al. NK cells in central nervous system disorders. J Immunol 2013; 190: 5355–5362.

    Article  CAS  PubMed  Google Scholar 

  30. Akira S, Uematsu S, Takeuchi O . Pathogen recognition and innate immunity. Cell 2006; 124: 783–801.

    Article  CAS  PubMed  Google Scholar 

  31. Lien E, Means TK, Heine H, Yoshimura A, Kusumoto S, Fukase K et al. Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide. J Clin Invest 2000; 105: 497–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Biswas SK, Lopez-Collazo E . Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol 2009; 30: 475–487.

    Article  CAS  PubMed  Google Scholar 

  33. Martin SF . Adaptation in the innate immune system and heterologous innate immunity. Cell Mol Life Sci 2014; 71: 4115–4130.

    Article  CAS  PubMed  Google Scholar 

  34. Ifrim DC, Quintin J, Joosten LAB, Jacobs C, Jansen T, Jacobs L et al. Trained immunity or tolerance: opposing functional programs induced in human monocytes after engagement of various pattern recognition receptors. Clin Vaccine Immunol 2014; 21: 534–545.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Tribouley J, Tribouley-Duret J, Appriou M . Effect of Bacillus Callmette Guerin (BCG) on the receptivity of nude mice to Schistosoma mansoni. C R Seances Soc Biol Fil 1978; 172: 902–904.

    CAS  PubMed  Google Scholar 

  36. Bistoni F, Vecchiarelli A, Cenci E, Puccetti P, Marconi P, Cassone A . Evidence for macrophage-mediated protection against lethal Candida albicans infection. Infect Immun 1986; 51: 668–674.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Jensen KJ, Larsen N, Biering-Sørensen S, Andersen A, Eriksen HB, Monteiro I et al. Heterologous immunological effects of early BCG vaccination in low-birth-weight infants in Guinea-Bissau: a randomized-controlled trial. J Infect Dis 2015; 211: 956–967.

    Article  CAS  PubMed  Google Scholar 

  38. Quintin J, Saeed S, Martens JHA, Giamarellos-Bourboulis EJ, Ifrim DC, Logie C et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 2012; 12: 223–232.

    Article  CAS  PubMed  Google Scholar 

  39. Püntener U, Booth SG, Perry VH, Teeling JL . Long-term impact of systemic bacterial infection on the cerebral vasculature and microglia. J Neuroinflammation 2012; 9: 146.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Bilbo SD . Neonatal infection-induced memory impairment after lipopolysaccharide in adulthood is prevented via caspase-1 inhibition. J Neurosci 2005; 25: 8000–8009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bland ST, Beckley JT, Watkins LR, Maier SF, Bilbo SD . Neonatal Escherichia coli infection alters glial, cytokine, and neuronal gene expression in response to acute amphetamine in adolescent rats. Neurosci Lett 2010; 474: 52–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ramos HJ, Lanteri MC, Blahnik G, Negash A, Suthar MS, Brassil MM et al. IL-1β signaling promotes CNS-intrinsic immune control of West Nile Virus infection. PLoS Pathog 2012; 8: e1003039–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chauhan VS, Sterka DG Jr., Furr SR, Young AB, Marriott I . NOD2 plays an important role in the inflammatory responses of microglia and astrocytes to bacterial CNS pathogens. Glia 2009; 57: 414–423.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Williamson LL, Sholar PW, Mistry RS, Smith SH, Bilbo SD . Microglia and memory: modulation by early-life infection. J Neurosci 2011; 31: 15511–15521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Cao M, Cortes M, Moore CS, Leong SY, Durosier LD, Burns P et al. Fetal microglial phenotype in vitro carries memory of prior in vivo exposure to inflammation. Front Cell Neurosci 2015; 9: 12.

    Article  Google Scholar 

  46. Ye M, Wang Q, Zhang W, Li Z, Wang Y, Hu R . Oroxylin A exerts anti-inflammatory activity on lipopolysaccharide-induced mouse macrophage via Nrf2/ARE activation. Biochem Cell Biol 2014; 92: 337–348.

    Article  CAS  PubMed  Google Scholar 

  47. Seong SY, Matzinger P . Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol 2004; 4: 469–478.

    Article  CAS  PubMed  Google Scholar 

  48. Matt U, Sharif O, Martins R, Knapp S . Accumulating evidence for a role of oxidized phospholipids in infectious diseases. Cell Mol Life Sci 2014; 72: 1059–1071.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Bekkering S, Quintin J, Joosten LAB, van der Meer JWM, Netea MG, Riksen NP . Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes. Arterioscler Thromb Vasc Biol 2014; 34: 1731–1738.

    Article  CAS  PubMed  Google Scholar 

  50. Manson J, Thiemermann C, Brohi K . Trauma alarmins as activators of damage-induced inflammation. Br J Surg 2012; 99 (Suppl 1): 12–20.

    Article  CAS  PubMed  Google Scholar 

  51. Ramlackhansingh AF, Brooks DJ, Greenwood RJ, Bose SK, Turkheimer FE, Kinnunen KM et al. Inflammation after trauma: Microglial activation and traumatic brain injury. Ann Neurol 2011; 70: 374–383.

    Article  PubMed  Google Scholar 

  52. Jorge RE, Robinson RG, Moser D, Tateno A, Crespo-Facorro B, Arndt S . Major depression following traumatic brain injury. Arch Gen Psychiatry 2004; 61: 42–50.

    Article  PubMed  Google Scholar 

  53. Fenn AM, Gensel JC, Huang Y, Popovich PG . Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia. Biol Psychiatry 2014; 76: 575–584.

    Article  CAS  PubMed  Google Scholar 

  54. Fleshner M, Campisi J, Amiri L, Diamond DM . Cat exposure induces both intra- and extracellular Hsp72: the role of adrenal hormones. Psychoneuroendocrinology 2004; 29: 1142–1152.

    Article  CAS  PubMed  Google Scholar 

  55. Weber MD, Frank MG, Tracey KJ, Watkins LR, Maier SF . Stress induces the danger-associated molecular pattern HMGB-1 in the hippocampus of male Sprague Dawley rats: a priming stimulus of microglia and the NLRP3 inflammasome. J Neurosci 2015; 35: 316–324.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Maslanik T, Mahaffey L, Tannura K, Beninson L, Greenwood BN, Fleshner M . The inflammasome and danger associated molecular patterns (DAMPs) are implicated in cytokine and chemokine responses following stressor exposure. Brain Behav Immun 2013; 28(C): 54–62.

    Article  Google Scholar 

  57. Fleshner M . Stress-evoked sterile inflammation, danger associated molecular patterns (DAMPs), microbial associated molecular patterns (MAMPs) and the inflammasome. Brain Behav Immun 2013; 27(C): 1–7.

    Article  Google Scholar 

  58. Cheng SC, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V et al. mTOR- and HIF-1 -mediated aerobic glycolysis as metabolic basis for trained immunity. Science 2014; 345: 1250684–1250684.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Yoshida K, Maekawa T, Zhu Y, Renard-Guillet C, Chatton B, Inoue K et al. The transcription factor ATF7 mediates lipopolysaccharide-induced epigenetic changes in macrophages involved in innate immunological memory. Nat Immunol 2015; 16: 1034–1043.

    Article  CAS  PubMed  Google Scholar 

  60. Maekawa T, Kim S, Nakai D, Makino C, Takagi T, Ogura H et al. Social isolation stress induces ATF-7 phosphorylation and impairs silencing of the 5-HT 5B receptor gene. EMBO J 2009; 29: 196–208.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Schaafsma W, Zhang X, van Zomeren KC, Jacobs S, Georgieva PB, Wolf SA et al. Long-lasting pro-inflammatory suppression of microglia by LPS-preconditioning is mediated by RelB-dependent epigenetic silencing. Brain Behav Immun 2015; 48(C): 205–221.

    Article  Google Scholar 

  62. Knuesel I, Chicha L, Britschgi M, Schobel SA, Bodmer M, Hellings JA et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat Rev Neurol 2014; 10: 643–660.

    Article  CAS  PubMed  Google Scholar 

  63. Talge NM, Neal C, Glover V, Early Stress TR Prevention Science Network F, Neonatal Experience on Cet alAntenatal maternal stress and long-term effects on child neurodevelopment: how and why? J Child Psychol Psychiatry 2007; 48: 245–261.

    Article  PubMed  Google Scholar 

  64. Glover V . Annual research review: prenatal stress and the origins of psychopathology: an evolutionary perspective. J Child Psychol Psychiatry 2011; 52: 356–367.

    Article  PubMed  Google Scholar 

  65. Van den Bergh BRH, Van Calster B, Smits T, Van Huffel S, Lagae L . Antenatal maternal anxiety is related to HPA-axis dysregulation and self-reported depressive symptoms in adolescence: a prospective study on the fetal origins of depressed mood. Neuropsychopharmacology 2007; 33: 536–545.

    Article  PubMed  Google Scholar 

  66. Sandman CA, Buss C, Head K, Davis EP . Fetal exposure to maternal depressive symptoms is associated with cortical thickness in late childhood. Biol Psychiatry 2015; 77: 324–334.

    Article  PubMed  Google Scholar 

  67. Depino AM . Early prenatal exposure to LPS results in anxiety- and depression-related behaviors in adulthood. Neuroscience 2015; 299: 56–65.

    Article  CAS  PubMed  Google Scholar 

  68. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA . Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 2001; 413: 732–738.

    Article  CAS  PubMed  Google Scholar 

  69. Giovanoli S, Engler H, Engler A, Richetto J, Voget M, Willi R et al. Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice. Science 2013; 339: 1095–1099.

    Article  CAS  PubMed  Google Scholar 

  70. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010; 330: 841–845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Berk M, Williams LJ, Jacka FN, Neil AO, Pasco JA, Moylan S et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med 2013; 11: 1–1.

    Article  Google Scholar 

  72. Maes M, Mihaylova I, Kubera M, Ringel K . Activation of cell-mediated immunity in depression: association with inflammation, melancholia, clinical staging and the fatigue and somatic symptom cluster of depression. Prog Neuropsychopharmacol Biol Psychiatry 2012; 36: 169–175.

    Article  PubMed  Google Scholar 

  73. Celik C, Erdem M, Caycı T, Ozdemir B, Akgul EO, Kurt YG et al. The association between serum levels of neopterin and number of depressive episodes of major depression. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 372–375.

    Article  CAS  PubMed  Google Scholar 

  74. Hauser P, Khosla J, Aurora H, Laurin J, Kling MA, Hill J et al. A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C. Mol Psychiatry 2002; 7: 942–947.

    Article  CAS  PubMed  Google Scholar 

  75. Dieperink E, Ho SB, Thuras P, Willenbring ML . A prospective study of neuropsychiatric symptoms associated with interferon-a-2b and ribavirin therapy for patients with chronic hepatitis C. Psychosomatics 2011; 44: 104–112.

    Article  Google Scholar 

  76. Capuron L, Ravaud A . Prediction of the depressive effects of interferon alfa therapy by the patient's initial affective state. N Engl J Med 1999; 340: 1370–1370.

    Article  CAS  PubMed  Google Scholar 

  77. Renault PF, Hoofnagle JH, Park Y . Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med 1987; 147: 1577–1580.

    Article  CAS  PubMed  Google Scholar 

  78. Schaefer M . Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups. Hepatology 2003; 37: 443–451.

    Article  CAS  PubMed  Google Scholar 

  79. Pariante CM, Orrù MG, Baita A, Farci MG, Carpiniello B . Treatment with interferon-α in patients with chronic hepatitis and mood or anxiety disorders. Lancet 1999; 354: 131–132.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

APS is supported by a National Institute for Health Research (NIHR) Biomedical Research Centre-Francis Crick Institute Clinical Training Fellowship. PAZ and AB are supported by the NIHR Maudsley Biomedical Research Centre.

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  1. Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

    A P Salam, A Borsini & P A Zunszain

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  1. A P Salam
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Correspondence to A P Salam.

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PAZ has received research funding from Johnson & Johnson as part of a program of research on depression and inflammation, and from the Medical Research Council (UK) and the Wellcome Trust for research on depression and inflammation as part of two large consortia that also include Johnson & Johnson, GSK, and Lundbeck. The remaining authors declare no conflict of interest.

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Salam, A., Borsini, A. & Zunszain, P. Trained innate immunity: a salient factor in the pathogenesis of neuroimmune psychiatric disorders. Mol Psychiatry 23, 170–176 (2018). https://doi.org/10.1038/mp.2017.186

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